In adult, reproductively active females, there is a continued increase in prevalence and propagation of metabolic disorders, such as obesity and type II diabetes. Beyond the harmful effects of these disorders on the adult population, there is increasing awareness of the potential long lasting negative influence of metabolic disorders of pregnant mothers on their offspring. Indeed, arguments have been made that chronic disease development maybe dramatically accelerated in children who were nursed in utero and early post-natally by obese and/or diabetic mothers. The underlying molecular mechanism of this early programming remains ill- defined. The central nervous system, and the hypothalamic arcuate nucleus in particular, has emerged as one of the key sites from which both behavioral and endocrine aspects of metabolism are governed. Our preliminary observations revealed the disruption of certain genes in specific subpopulation of arcuate nucleus neurons underlie the emergence of altered metabolic phenotypes not dissimilar to those emerging in offspring of obese or diabetic mothers. Our central hypothesis stem from these investigations and propose that altered intracellular signaling in the arcuate nucleus melanocortin system triggered by insulin is a major component in the etiology of subsequent metabolic disturbances. We will further strengthen this hypothesis by investigations proposed here on wild type and genetically altered mice. We will address the following specific aims: Aim 1 Determine the cellular changes in AgRP and POMC neurons in the offspring of obese/diabetic mothers. Aim 2 Unveil the responses of AgRP and POMC neurons to feeding, fasting, leptin, insulin and glucose in the offspring of obese/diabetic mothers. Aim 3 Assess the effect of targeted mutations of insulin and leptin signaling in subpopulations of arcuate nucleus neurons on circuit development and metabolic phenotype of offspring derived from obese/diabetic mothers. The execution of the above aims will proved molecular explanations for the better understanding of the etiology of metabolic disorders in association with in utero environment of obese and diabetic mothers. PUBLIC HEALTH RELEVANCE: The proposed project will analyze the role of pregnancy on the development of obesity and diabetes of the offspring. This is a highly relevant area of medical research as the majority of women are overweight during pregnancy, which may be a main reason for the increasing obesity epidemic and the increased prevalence of type II diabetes.